Search

In both 5- and 15-min data, FI was significantly higher in malignant tissues than in benign tissues. The diagnostic accuracy was similar at 5 and 15 min. Therefore, the 5-min FI was enough applying in the further analyses.

Background: Identification of promising biomarkers that predict the prognosis of patients with breast cancer is needed. In this study, we hypothesised that the expression of the epithelial–mesenchymal transition-related biomarker plastin3 (PLS3) in peripheral blood could be a prognostic factor in breast cancer. Methods: We examined PLS3 expression in breast cancer cell lines with epithelial and mesenchymal traits and in circulating tumour cells (CTCs) obtained from the peripheral blood of breast cancer patients. We investigated PLS3 expression in the peripheral blood of 594 patients with breast cancer to evaluate the clinical significance of PLS3 expression. Results: Robust PLS3 expression was observed in different breast cancer cell lines (Hs578t, MCF-7, MDA-MB-468, and MDA-MB-231) as well as in a bone marrow derived cancer cell line (BC-M1). In both the training (n=298) and validation (n=296) sets, PLS3 expression was observed in CTCs of patients with breast cancer. PLS3-positive patients showed significantly poorer overall and disease-free survival than PLS3-negative patients (P=0.0001 and 0.003, respectively). Subset analysis revealed that this prognostic biomarker was relevant in patients with stage I–III cancer, particularly in patients with luminal-type and triple-negative-type tumours. Conclusions: These data demonstrated that PLS3 was expressed in CTCs undergoing the epithelial–mesenchymal transition in patients with breast cancer. Furthermore, PLS3 may be an excellent biomarker for identifying groups at risk of recurrence or with a poor prognosis.

We report on a case of a female patient diagnosed with inflammatory pseudotumor of the liver in association with spilled gallstones 3 years after laparoscopic cholecystectomy for calculous acute cholecystitis. She was asymptomatic, but CT revealed an intrahepatic mass and two other extrahepatic masses between the liver and the diaphragm. Furthermore, diffusion-weighted MRI and PET suggested all three lesions could be malignant tumors. As the preoperative diagnosis was intrahepatic cholangiocellular carcinoma with peritoneal disseminations, we performed a posterior segmentectomy of the liver combined with partial resection of the diaphragm. Histological examination showed the intrahepatic tumor was an inflammatory granuloma with abscess formations. There were bilirubin stones between the liver and the diaphragm. Therefore, the tumor was diagnosed as inflammatory pseudotumor of the liver in association with spilled gallstones. In conclusion, the liver tumor emerged after laparoscopic cholecystectomy and may involve inflammatory pseudotumor of the liver in association with spilled gallstones.

We report on a case of a female patient diagnosed with inflammatory pseudotumor of the liver in association with spilled gallstones 3 years after laparoscopic cholecystectomy for calculous acute cholecystitis. She was asymptomatic, but CT revealed an intrahepatic mass and two other extrahepatic masses between the liver and the diaphragm. Furthermore, diffusion-weighted MRI and PET suggested all three lesions could be malignant tumors. As the preoperative diagnosis was intrahepatic cholangiocellular carcinoma with peritoneal disseminations, we performed a posterior segmentectomy of the liver combined with partial resection of the diaphragm. Histological examination showed the intrahepatic tumor was an inflammatory granuloma with abscess formations. There were bilirubin stones between the liver and the diaphragm. Therefore, the tumor was diagnosed as inflammatory pseudotumor of the liver in association with spilled gallstones. In conclusion, the liver tumor emerged after laparoscopic cholecystectomy and may involve inflammatory pseudotumor of the liver in association with spilled gallstones.

A novel human gene, designated HRad17, was identified as the human homologue of the Rad17 of Schizosaccharomyces pombe and Rad24 of Saccharomyces cerevisiae. In yeast, these genes play a critical role in maintaining genomic stability. The aim of this study was to evaluate the expression of HRad17 in human breast cancer.We investigated HRad17 mRNA expression in 64 cases of human breast cancer by means of reverse-transcription-PCR, in situ hybridization, and immunohistochemistry.The HRad17 mRNA was overexpressed in 35 cases (54.7%). Twenty-four (68.6%) of 35 cases with HRad17 overexpression in cancer tissues were node-positive, whereas only 8 (27.6%) of 29 cases without HRad17 overexpressions were node-positive. The expression of HRad17 mRNA correlated with both lymph node metastasis (P = 0.001) and high Ki67 labeling index (P = 0.006). Although not significantly different, expression of HRad17 mRNA tended to correlate with tumor size (P = 0.06) and expression of mutant p53 protein (P = 0.10). Furthermore, expression of HRad17 mRNA was an independent predictor of axillary lymph node metastasis as well as of lymphatic permeation by multivariate analysis (P0.0001).Our study demonstrates that HRad17 might be related to the development of lymph node metastasis in human breast cancers. Although its function still remains unclear, the expression of HRad17 mRNA could open up a new window for the diagnostic staging and treatment of human breast cancers.

Human esophageal carcinomas occur more frequently in males, suggesting that androgens may play a role in the regulation of gene expression associated with malignant transformation. We previously established an androgen-sensitive squamous cell carcinoma line, KSE-1, from a male patient with esophageal cancer; recently a novel isoform of human fibroblast growth factor 8 (FGF8f, isoform FGF8b) was identified and expressed following androgen stimulation of KSE-1 cells. The predicted amino acid sequence of FGF8f contained an additional 29 amino acids when compared to FGF8b. Flutamide, an androgen antagonist, inhibited both FGF8b and FGF8f transcription in a dose-dependent manner. Tissue analysis from tumors revealed FGF8b expression in 24 of 41 male, but in 0 of 9 female esophageal carcinomas (58.5%), and none in adjacent normal esophageal mucosa. In addition, FGF8f was detected in 9 of 24 FGF8b-positive tumors (37.5%), and this observation was significantly associated with a poor prognosis (P0.001). Our observations suggest that androgenic exposure will induce FGF isoforms in tumor cells, and expression of these growth factors is associated with the prevalence and prognosis of esophageal carcinoma in males.

After a single dose of cisplatin, the ability of peripheral blood mononuclear cells (PBMC) to generate lymphokine-activated killer (LAK) cells was significantly augmented in cancer patients. Based on this clinical finding, the patients with locally advanced esophageal carcinoma were thus treated with a combination of cisplatin and low-dose interleukin-2 (IL-2) in a neoadjuvant setting. Four patients with squamous cell carcinoma of the esophagus (T3 or T4 disease) were preoperatively treated with a regimen consisting of 50 mg/m2 cisplatin on day 1, followed by IL-2 from day 4 through day 8, when the ability of PBMC to generate LAK cells had been shown to be significantly augmented. After two to four courses of the preoperative therapy, one patient achieved a histologic CR, one showed PR and one MR. No severe toxicity was encountered. All patients thereafter underwent surgery. The median survival of these patients was 47.5 months and three of the patients had been disease free for 43 to 62 months after the initiation of the therapy. The combination of cisplatin and low-dose IL-2 administered in a neoadjuvant setting seems to result in an improved survival of locally advanced squamous cell carcinoma of the esophagus.

We designed a chemoimmunotherapy regimen with a single dose of mitomycin C (MMC) followed by subsequent OK-432 injections, since the ability of peripheral blood mononuclear cells (PBM) to generate OK-432 activated killer cells had previously been shown to be augmented by MMC in cancer patients. We herein report on a case with far advanced gallbladder carcinoma who demonstrated a remarkable response to this chemoimmunotherapy, and thus underwent a curative resection. A 67 year-old Japanese woman was diagnosed as having gallbladder carcinoma with invasion to the liver and portal vein, as well as obvious lymph node metastasis. Since these findings suggested the tumor to be unresectable at that time, our chemoimmunotherapy regimen with MMC and OK-432 was administered. After four courses of therapy, a computed tomography (CT) scan revealed the disappearance of both tumor invasion to the surrounding organs and lymph node metastasis, which therefore prompted us to attempt a radical tumor resection. The histology of the resected specimen revealed that the majority of cancer cells had been killed by the pre-operative therapy and that only remnants of viable cancer cells were found in a part of the neck of the gallbladder and in 2 regional lymph nodes. This experience thus suggests the effectiveness of our chemoimmunotherapy regimen against gallbladder carcinoma.

It is important to detect genes that may be good prognostic markers for colon cancer patients. With this in mind, we identified the motility related protein-1 (MRP1/CD9) gene in human colon tissues. The aim of this study was to clarify the significance of MRP1/CD9 gene expression in human colon cancers. We performed the differential mRNA display technique between tumor/normal paired samples of the colon and identified MRP1/CD9. Eighty-two surgical specimens of primary colorectal cancer were analyzed by means of reverse transcription-PCR for the MRP1/CD9 gene. Its expression status and clinicopathological variables were analyzed univariately and multivariately. The MRP1/ CD9 mRNA expression was positive in 56 cases and negative in 26 cases. The MRP1/CD9 negative cases showed a significantly higher frequency of venous-vessel invasion and liver metastasis, or a worse prognosis than the MRP1/CD9 positive cases (P0.05). Multivariate analysis with the Cox regression model disclosed that MRP1/CD9 expression was an independent prognostic factor distinct from the lymph node status. The findings imply that the study of MRP1/CD9 expression may be useful for predicting prognosis of patients with colorectal cancer.

The 12 members of the human melanoma antigen-encoding (MAGE) gene family encode tumor-specific peptide antigens. Some antigens coded by the MAGE genes are potentially useful for cancer-specific immunotherapy. However, little information on the expression of these genes in human colon carcinomas is available. We investigated the expression of 10 of the 12 genes in human colon tissue.Eighty pairs of tumor and normal tissue samples from the human colon were studied by means of reverse transcription-polymerase chain reaction.None of the genes was expressed in the 80 control samples of normal tissue. On the other hand, expression was recognized in tumor samples, ranging from 5% of samples for MAGE-6 to 44% for MAGE-8. Seventy of the 80 tumor samples (88%) expressed at least 1 of the 10 MAGE genes. The frequency of liver metastasis was significantly higher in cases with tumor samples that expressed MAGE-3 than in those that did not express this gene. This tendency was not observed for other members of the MAGE gene family. No significant differences were observed in the other clinicopathologic factors between any MAGE-positive and -negative tumor cases.The MAGE genes were exclusively expressed in carcinoma tissues and not in normal tissues of the colon. The finding that nearly 90% of tumors expressed at least one MAGE gene indicates the possible clinical use of this gene for both immunotherapy and molecular diagnosis.

MAGE genes code tumor antigens that are recognized by cytolytic T lymphocytes and have been shown to be expressed in various malignant tumors. However, there is still little information on the expression of the MAGE gene family except for reports of MAGE-1 and -3. In this study, we therefore investigated the expression of MAGE-4, -6, -8, -9, -10, -11 and -12, as well as MAGE-1, -2 and -3 in both cell lines and surgical samples of gastric carcinoma, using reverse transcriptionPCR. Of the investigated 11 cell lines, MAGE-4, -6, -8, -9, -10, -11 and -12 were detected in 8 (73%), 6 (55%), 2 (18%), 59 (44%), 6 (55%), 4 (36%), and 7 (64%), respectively. No expression of these genes was seen in any of the 54 samples of normal gastric tissue. In contrast, the tumor tissue samples were found to express MAGE-4, -6, -8, -9, -10, -11, and -12 in 18 (33%), 13 (24%), 6 (11%), 10 (19%), 5 (9%), 13 (24%), and 10 (19%), respectively. Forty-four (82%) of 54 gastric tumors expressed at least one of these genes. No significant correlation was observed between the expression of MAGE genes and any specific clinicopathological factors. These results may hopefully prove to be useful in developing strategies for tumor-specific immunotherapy of gastric carcinoma using MAGE gene products.

Patients with collagen diseases are generally regarded as high-risk surgical candidates.To evaluate the feasibility of epidural anesthesia and to determine the risk factors in abdominal surgery for patients with collagen diseases, 20 patients with collagen diseases who underwent elective abdominal surgery were examined for their surgical outcomes and clinical characteristics. Among the 20 cases, 12 received epidural anesthesia alone without endotracheal intubation, 3 received general anesthesia only, 4 received general anesthesia with epidural anesthesia and one received lumbar anesthesia.Only one patient receiving epidural anesthesia died after operation. The mortality in patients receiving epidural anesthesia was 8.3% (1/12) while the overall mortality was 5.0% (1/20). No significant difference was observed either in the mortality or incidence of postoperative complications among the 4 groups according to the method of anesthesia. Patients with a dysfunction of the vital organs more often had postoperative complications than those without a dysfunction of the vital organs (p = 0.043).Although only a small number of patients were included in this study, these results suggested that 1) elective abdominal surgery can be as safely performed under epidural anesthesia alone as with general anesthesia even for patients with collagen diseases, and 2) the patients with collagen diseases, who preoperatively showed a dysfunction of the vital organs, might be at a higher risk for abdominal surgery.

To improve the surgical outcome in patients with radiation enteritis, 18 female cases were analyzed. Out of the 18 cases, 3 (16.7%) were treated conservatively while 15 (83.3%) underwent surgical procedures. Thirteen out of 14 patients (92.8%) with ileus underwent an operation. The overall mortality was 22.2% (4 out of 18 cases). However, no significant difference in the mortality between the operated and non-operated cases was observed. Although an analysis of the 15 operated cases did not reveal any significant factors that might have affected the prognosis, all four patients who underwent a bypass operation showed a good postoperative course, with only one excepting being a patient suffering from malnutrition. Although only a small number of patients were included in this study, these results suggest that 1) surgeons should not hesitate to operate on patients with radiation enteritis demonstrating ileus, and 2) a bypass operation may be one surgical alternative in the presence of massive adhesion or for patients at high risk for a standard operation.

The MAGE, BAGE, and GAGE genes code for distinct antigens that are recognized by autologous cytolytic T lymphocytes. We investigated the expression of these genes in both cell lines and surgical samples of gastric carcinoma, using reverse transcription-PCR. Furthermore, the induction of these genes by 5-aza-2'-deoxycytidine (DAC), a demethylating agent, was also examined in several cell lines. Of 11 cell lines, BAGE, GAGE1-6, GAGE1-2, MAGE-1, and MAGE-3 were detected in 7 (64%), 4 (36%), 3 (27%), 8 (73%), and 8 (73%) cell lines, respectively. After the in vitro treatment of the negative cell lines with DAC, the expression of these genes became positive in 46 to 91% of these cell lines. No expression of these genes was seen in any of the 57 samples of normal gastric tissue. In contrast, the tumor tissue samples expressed BAGE, GAGE1-6, GAGE1-2, MAGE-1, and MAGE-3 in 13 (23%), 9 (16%), 6 (11%), 25 (44%), and 23 (40%) tissue samples, respectively. Thus, at least one of these genes was expressed in 35 (61%) of 57 carcinomas. An analysis of the relationship between clinicopathological factors and the expression of these genes revealed that either BAGE or one of these genes was more frequently expressed in histologically intestinal-type than in diffuse-type carcinomas. Our results suggest that, because of the higher expression of these genes and the possible induction of these genes by DAC, patients with gastric carcinoma may, therefore, be potential candidates for tumor-specific immunotherapy directed against these antigens.

We reviewed the clinical significance of genetic instability or replication error (RER) in human gastrointestinal carcinomas. The RER positive tumors are seen in about 10-30% of these carcinomas. The RER positive esophageal carcinomas tend to show unusual histologic subtypes such as adenocarcinoma or small cell carcinoma. The RER positive gastric carcinomas show no specific characteristics in our study while several investigators describe the high frequency of poorly differentiated adenocarcinomas of the higher frequency of advanced carcinomas. The RER positive colorectal carcinomas show a tendency to show poorly differentiation to occur in the proximal colon, to have no lymph node metastasis and to show good prognosis. Several candidate genes that may correlate with RER are shown.

There are few DNA-based studies that detect cancer micrometastases in lymph nodes. We have assayed for the specific detection of carcinoembryonic antigen (CEA)-expressing carcinoma cells in the lymph nodes of patients with gastrointestinal or breast carcinomas. A CEA-specific nested reverse transcriptase (RT)-PCR assay was optimized using limiting dilutions of a CEA-positive cancer cell line mixed with normal lymphocytes. The expression of CEA mRNA was studied in 100 carcinoma tissues, 75 normal mucosal tissues, and 15 lymph nodes from patients with cholelithiasis. Each of 117 lymph nodes from 13 patients with carcinoma was divided into two pieces: one was used for histological examination and the other for RT-PCR, and the results were compared. The sensitivity ratio was one CEA-expressing cancer cell detected in 1 x 10(5) normal lymphocytes. All carcinoma tissues and normal mucosal tissues expressed CEA mRNA, while no amplification was detected in any control lymph nodes. Thirty of 117 lymph nodes were histologically involved by carcinoma cells, and all of these yielded the expected product by RT-PCR. Of the remaining 87 histologically negative nodes, CEA mRNA was detected in 47 lymph nodes by RT-PCR. The positive rate increased from 26% by histological examination to 66% by RT-PCR. The assay by CEA-specific nested RT-PCR is not only sensitive but widely applicable for the detection of cancer micrometastases in lymph nodes. This method may lead to an earlier diagnosis and treatment of patients with subclinical lymph node metastasis.

To obtain a better understanding of the role of genetic instability in developing gastric cancer, it is of great interest to examine microsatellite alterations in synchronous multiple gastric cancers that are thought may have the same genetic background and the same microenvironment of the stomach. We report our experience with two patients with synchronous multiple gastric cancers; patient 1 showed two carcinomas in the stomach, whereas patient 2 showed two carcinomas and two adenomas in the stomach. We examined the DNAs from the two cases for microsatellite instability and expected that the status of microsatellite instability in each tumor from the same stomach would be the same. However, patient 2 revealed heterogeneity in the microsatellite instability, i.e., an early cancer that showed some apparent alterations, whereas the other advanced cancer and two adenomas did not. On the other hand, neither of the two carcinomas in patient 1 showed microsatellite instability. To our knowledge, there has been no previous report of microsatellite instability in multiple gastric cancers. In this report, we describe a case that revealed such a heterogeneity of the microsatellite instability, in which the carcinogenic process of each tumor may undergo different genetic alterations even under the same genetic conditions and background.

To evaluate the efficacy of a single application of epidural anesthesia without endotracheal intubation for pancreaticoduodenectomy (PD), the data on 30 patients who underwent PD were analyzed for their operative morbidity and mortality. These patients were classified into two groups according to the type of anesthesia performed: 15 received epidural anesthesia alone (Group I) and 15, general anesthesia under endotracheal intubation (Group II). The clinical characteristics of the patients in both groups were comparable at the time of operation, except that Group I included a significantly larger proportion of elderly patients than Group II (p0.05). Postoperative pulmonary complications (PPCs) occurred in 5 (33.3%) of the Group II patients, especially in elderly patients who underwent lengthy operations, whereas no such complications occurred in the Group I patients (p0.05), even in elderly patients with a long operating time. The curability of the malignant tumors and the incidences of other complications were not significantly different between the two groups. These findings suggest that a single application of epidural anesthesia is effective in preventing PPCs when performing a time-consuming PD, especially in elderly patients.

The MTT assay in agarose, a simple colorimetric test performed in double-layer agarose, has been evaluated for chemosensitivity testing of fresh tumor samples from human cancers in comparison with the MTT assay. The absorbance of cells from fibroblast cell lines or normal tissues was markedly reduced in agarose. The chemosensitivity of cells from a carcinoma cell line or fresh tumor tissues was not apparently affected by the presence of almost 50% of fibroblast or nonmalignant cells in the MTT assay in agarose, whereas it did so in the MTT assay. The frequency of the differences between chemosensitivity of fresh tumor samples in both assays was increased, when the tumor tissue cells contained a higher proportion of nonmalignant cells, i.e. vimentin-positive cells. In 173 patients with various carcinomas, in vitro sensitivity to 7 drugs in the MTT assay in agarose was significantly greater than that in the MTT assay. Further, the MTT assay in agarose had a higher accuracy for prediction of either sensitivity or resistance than the MTT assay in a total of 38 in vitro-in vivo correlations. These results indicated that the MTT assay in agarose was a more suitable technique for the application to chemosensitivity of fresh tumor samples from patients with various carcinomas as compared to the MTT assay.

Interleukin-6 (IL-6) plays a central role in the acute phase of inflammation after surgical injury. The serum concentration of IL-6 increases during an operation. The mechanisms of this increase in the serum IL-6 level, however, has not yet been fully clarified.To determine the possibility of production of IL-6 at the operative wound site and its regulation by humoral factors in surgical patients, the IL-6 secretion of biopsied skin obtained from an operative wound both before and after the operation were quantitated by using organ culture techniques.When skin explants obtained from the uninjured skin were cultivated and the amounts of IL-6 secreted into the culture medium were measured, IL-6 secretion increased exponentially during culture, which indicated that the stress of the skin incision induced IL-6 production. The skin specimens obtained from the operative wounds postoperatively secreted a significantly larger amount of IL-6 than those obtained from uninjured skin either preoperatively or postoperatively, implying that skin at the site of the operative wound had been more sensitized to produce IL-6 because of the surgical injury. The IL-6 secretion by skin explants was significantly enhanced either by tumor necrosis factor or interleukin-1, while it was inhibited by corticosteroids.Interleukin-6 production at the site of the operative wound is partly responsible for the elevation of the serum IL-6 level during the operation. Organ cultures of the skin explants may provide a feasible system for research on the cytokine networks in surgical patients.

To evaluate the efficacy of a single application of epidural anesthesia without endotracheal intubation for elderly patients over 80 years of age, the data on 108 patients who underwent abdominal surgery were analyzed for the occurrence of postoperative complications. These patients were classified into two groups according to the type of anesthesia performed: 66 received epidural anesthesia alone (Group I) and 42, general anesthesia under endotracheal intubation (Group II). There were no lethal pulmonary complications in Group I, whereas 2 patients (4.8%) died of respiratory failure resulting from pulmonary complications in Group II. The incidence of postoperative pulmonary complications in Group I was 6.1%, which was significantly lower than the 28.6% observed in Group II (p0.005). The occurrence of pulmonary complications in Group I was not related to the operating time, while pulmonary complications frequently occurred in patients who underwent lengthy operations in Group II. These findings suggest that a single application of epidural anesthesia would improve the overall safety in performing abdominal surgery in elderly patients over 80 years of age.

The cytotoxic effect of 5-FU (5-fluorouracil) was demonstrated to be enhanced by hyperthermia after treatment with 5-FU at even a comparatively low dose over fairly long periods. The cytotoxic effect of the combined treatment with 42 degrees C-hyperthermia and 1 microgram/ml 5-FU for 48 hrs, the cytotoxic effect of 42 degrees C-hyperthermia and 5 micrograms/ml 5-FU for 24 hrs, and the cytotoxic effect of 43 degrees C-hyperthermia and 1 and 5 micrograms/ml 5-FU for 8 hrs were studied. The maximally enhanced rate of 42 degrees C-hyperthermia after 5-FU treatment for 96 hrs was 48% after a 1 microgram/ml 5-FU treatment and 150% after 45 hrs with the 5 micrograms/ml 5-FU treatment. The maximally enhanced rate of 43 degrees C-hyperthermia after 5-FU treatment was 170% after 45 hrs with 1 microgram/ml 5-FU treatment and 180% after 24 hrs with 5 mg/ml 5-FU treatment. When V-79 cells were treated at the same temperature, the maximally enhanced rate with 1 microgram/ml 5-FU was almost equal to that of 5 micrograms/ml. Moreover, when each maximally enhanced rate was equalized, each concentration of FU (RNA)/RNA practically became equal, i.e., when the maximally enhanced rates were approximately 150 and 170-180%, FU (RNA)/RNA concentrations were about 40 and 15 ng/mg RNA, respectively. We thus concluded that FU (RNA)/RNA concentration might play an important role as an indicator of the effect of the combined treatment of 5-FU and hyperthermia.

We designed a simple and reliable method of intrahepatic biliary drainage for patients with obstructive jaundice owing to a recurrent gastric cancer. This approach can be used for selected patients treated by partial gastrectomy and reconstructive surgery, using the Billroth II procedure and antecolic anastomosis. Anastomosis between the intrahepatic bile duct and the afferent jejunal loop is performed at the anterior edge of the liver, thus facilitating the prevention of recurrence of jaundice caused by tumor infiltration. Application of this technique led to a long-term palliation, control of the jaundice and a fairly normal life.

A comparative study of two different species of a fluorouracil assay was conducted on 11 patients who had carcinoma that was deemed unresectable after the surgical operation. For these patients FU at a dose of 10 mg/kg was intravenously administered before operation, and portions of the tumors were resected within 120-150 min to assay both the (FU)RNA/RNA and FU/protein. After surgery, all patients were given FU alone either intravenously or orally. The FU, which was in an acid-soluble material (FU/protein), was not related to the antitumor effect of FU. However, the FU in RNA [(FU)RNA/RNA)] was found to be related to the antitumor effect of FU. When the concentration of (FU)RNA/RNA was above approximately 200 ng/mg, FU was effectual in unresectable carcinomas. It is probable that the (FU)RNA/RNA may be more suitable than FU/protein for predicting the antitumor effect of FU.

In order to accurately determine sex hormone dependency and hormone responsiveness in human esophageal carcinoma, the effects of sex hormones on the growth of esophageal carcinoma cell lines, KSE-1 and KSE-2 cells, were examined in vitro and in vivo. Cell proliferation of cultured KSE-1 cells was inhibited by treatment of estradiol and enhanced by dihydrotestosterone (DHT), whereas KSE-2 cells were unaffected by these sex hormones. The heterotransplanted tumors of KSE-1 cells in nude mice possessed estrogen receptor (ER) and androgen receptor (AR), while the tumors of the KSE-2 cells had neither ER nor AR. When the tumor growth rates and serum hormone levels were monitored during the continuous administration of either estradiol or DHT, no significant differences were observed in either the serum hormone levels or tumor growth rates between male and female mice. The administration of estradiol significantly inhibited the growth of ER-positive and AR-positive KSE-1 tumors in both males and females in conjunction with an increase in the estradiol levels and a decrease in the DHT levels in the serum. However, the growth of ER-negative and AR-negative KSE-2 tumors was not influenced by either estradiol or DHT administration. These results suggest that the in vivo growth of human esophageal carcinoma cells with sex hormone receptor is influenced by circulating hormone levels and can be manipulated by systemic estradiol administration.

We have attempted to develop an in vitro assay system for predicting estradiol sensitivity of clinical cancer cells by measuring the effects of estradiol on the net DNA synthesis of primary culture cells. Superinoculation of neoplastic and normal cells onto confluent monolayers of a contact-sensitive cell line, which have been designated as contact-sensitive plates (CSPs), resulted in both the specific growth of the neoplastic cells and the growth inhibition of contact-sensitive normal cells. The applicability of CSPs to an estradiol sensitivity test was examined in the known estradiol-sensitive, estrogen receptor-possessing cell lines, MCF-7 breast cancer and KSE-1 esophageal cancer cells. The responses of each cancer cell to estradiol were sufficiently evaluated in this assay and clearly demonstrated stimulative and inhibitive growth regulatory effects of the estradiol in MCF-7 and KSE-1 cells, respectively. A total of 38 clinical carcinomas (33 of the breast and 5 of the esophagus) were tested for their estradiol sensitivity. A statistically significant increase of cancer cell growth (P less than 0.1) in nontreated culture from the 48th to the 96th h of the primary culture on CSPs was observed in 28 of 38 overall cases (73.7%), and the evaluable data were obtained within 5 days by a sampling of 5 X 10(3) cancer cells. Most of the breast carcinomas exhibited a positive correlation between the growth-stimulative effect of estradiol in this assay and the estrogen receptor levels in the resected specimens. On the other hand, a clinical case of esophageal cancer with an estrogen receptor showed a growth inhibition of primary carcinoma cells by estradiol treatment. These results therefore indicate the feasibility of predicting individual tumor response to estradiol by using a rapid sensitivity test in vitro.

Hyperthermia alone had a lethal effect on V-79 cells. Temporary exposure to hyperthermia resulted in substantial decreases in cell growth, in a time (20-120 min)- and temperature (39-44 degrees C)-dependent manner. A precipitous fall in cell growth occurred when cells were incubated at temperatures between 42 and 43 degrees C. Concomitant application of hyperthermia, bleomycin and irradiation (hyperthermochemoradiotherapy) led to a maximal effect, compared with findings in cells treated with a single or two modalities, in vitro as well as in vivo and in clinical cases. To produce a similar situation of tumor cell growth in vivo, multicellular tumor spheroids (MTS) were developed by culturing tumor cells on soft agar. The effect of various treatments on the cells was then determined. Hyperthermia had a greater effect on the inner layer (hypoxic state) of MTS than on the outer layer, while radiotherapy was more effective on the outer layer (aerobic state). The synergistic effect of the combination with hyperthermia and irradiation was exhibited in all layers of MTS. Hyperthermochemoradiotherapy may prove to be an effective and safe form of adjuvant therapy for treating clinical carcinoma.

Cefminox (CMNX, MT-141) was administered to 7 cases with postoperative infections including subphrenic abscess and wound abscess, and the clinical effect was good in 2 cases, fair in 2, poor in 2 and unknown in 1. A daily dose was 2 g in 7 cases. The maximum total dose and duration were 22 g and 11 days respectively. Side effect which was observed during the test period was 1 case of drug eruption. No abnormal laboratory findings related to this drug were noted.

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor-promoting phorbol diester, were determined with regard to the induction of esophageal cancer in Wistar rats following a low-dose initial administration of the esophageal carcinogen N-amyl-N-methylnitrosamine [(AMN) CAS: 13256-07-0]. The induction of esophageal cancer was enhanced by TPA given in drinking water after AMN administration; i.e., the incidence of developing esophageal cancers and the multiplicity (number of esophageal cancers per rat) were significantly higher in groups given TPA solution orally after an oral administration of AMN than in those given the AMN solution alone. The enhancement of carcinogenesis with TPA was not affected by the interval between the administration of AMN and the administration of TPA. However, pretreatment with TPA before AMN administration did not enhance the induction of esophageal cancer. Neoplasms were not detected in groups given only TPA or tap water. Because this approach is similar to the phenomenon of two-stage carcinogenesis in the skin, it should provide a meaningful experimental model for studying two-stage carcinogenesis in the esophagus.

Preoperative irradiation for carcinoma of the esophagus is tentatively recommended in many, but not all, institutes. For precise appraisal of the effect of preoperative irradiation for carcinoma of the esophagus, the effects of preoperative irradiation, as related to mortality and the long term results, were evaluated in 167 patients who underwent subtotal esophagectomy. Although postoperative pulmonary complications occurred at a higher rate in patients given irradiation preoperatively, the mortality was much the same in irradiation and nonirradiation groups. In 15 (14.4 per cent) of 104 patients given radiation therapy preoperatively, no viable cancer cells were present in the resected tissues and the five year survival rate of these patients was 45.1 per cent. Thus, when the cancer cells are completely damaged, the survival time is extremely enhanced. The findings of our study suggest that the aim of preoperative irradiation should be a complete destruction of the cancer cells.

We report a case of carcinoma originating from accessory breast tissue of axilla and review 33 reported cases of carcinoma in heterotopic breast tissue. Although the incidence of accessory breast cancer is not high, early diagnosis and treatment are necessary, keeping in mind the possibility of this carcinoma when subcutaneous nodules of uncertain origin are found around the breast. Surgical treatment which must at least include wide local extirpation including the surrounding tissues and dissection of the axillary lymph nodes is necessary and adjunctive chemotherapy and irradiation appear to be useful.

We have developed a qualitative and quantitative assay system for detecting cells lacking postconfluence inhibition of cell division (contact insensitivity, CS-) in golden Syrian hamster embryo cells in culture by measuring the number of cells able to form colonies on a lethally irradiated, confluent monolayer of a contact-sensitive established cell line. A subpopulation in normal low-passage cultures of golden Syrian hamster embryo cells temporarily exhibits this CS- phenotype at very low frequency (approximately 4 x 10(-3)) but quickly loses the property within a few passages in vitro. This phenotype is invariably exhibited by various tumorigenic cell lines at very high frequency (7 to 50 x 10(-2)) and appears to correlate with the anchorage-independent growth phenotype. The temporal acquisition of the CS- phenotype by tertiary-passage golden Syrian hamster embryo cells following exposure to N-methyl-N'-nitro-N-nitrosoguanidine was examined. Cells with a stably heritable CS- phenotype are detected after approximately 20 posttreatment population doublings. In contrast, anchorage-independent cells are not detected until 35 to 95 posttreatment population doublings. These CS- cells appear to be preneoplastic cells, since clonally isolated CS- cells did not exhibit anchorage-independent growth until further passaging in vitro. The results suggest that acquisition of the CS- phenotype represents an early stage in neoplastic progression.

Biopsy tissues from a 68-year-old Japanese man with metastases to axillary lymph nodes of a recurrent esophageal carcinoma were adapted to cell culture conditions and a continuously growing tumor cell line was developed. Immunohistochemical staining revealed that these cells contained keratinous material and the electron microscopic study revealed the presence of tonofilaments. Thus, this line, designated the KSE-1 line, was considered to have originated from metastatic squamous cell carcinoma of the esophagus. This line has a binding content of 4.2 fmol/mg protein for the estrogen receptor and 2.2 fmol/mg protein for the testosterone receptor. By measurement of cell number and thymidine incorporation, the growth rate of this line was found to be moderately responsive to these hormones, being inhibited by estrogen and enhanced by testosterone at concentration levels between 10(-13) and 10(-8) and 10(-13) and 10(-6) mg/ml, respectively.

Gastric cancer associated with pregnancy is most often associated with a poor prognosis because the cancer stage is usually advanced at the time of diagnosis. The symptoms are frequently masked by factors related to the normal pregnancy and diagnostic approaches are restricted by physical and psychological clinical events. The authors treated a 30-year-old woman at 35 weeks of gestation. She had episodes of hematemesis and a prompt diagnosis of early gastric cancer was made following observations using a gastroduodenal fiberscope. A living normal child was delivered following oxytocin-induced labor and, 18 days later, curative resection for the gastric cancer was done. The patient has been doing well for over 16 months at this writing, with no evidence of recurrence. Based on the author's experience and a review of the literature, they conclude that early gastric cancer detected during pregnancy has a satisfactory prognosis and that use of the gastrofiberscope facilitates an early diagnosis in a pregnant subject with untoward symptoms of the GI tract.

The antipyretic effects of heparin on fever of unknown origin were investigated in three patients after hepatectomy. The elevated temperatures in these patients seemed to be due to a pyrogen as no definite evidence of infection was obtained. Heparin (100-150 IU per kg of body weight) was given every eight or 12 hours subcutaneously, and fever disappeared in all three patients. This antipyretic effect of heparin was considered due to the acceleration of the pyrogen clearing system. The major thrust of this report is the clinical usefulness of heparin for the management of pyrexia of unknown origin.

Mediastinal lymphography was carried out preoperatively upon 15 patients with carcinoma of the thoracic part of the esophagus. The tracheal bifurcation was punctured, and contrast medium was slowly injected. Mediastinal lymphograms were taken within 24 hours and, again, three and seven days after this injection. The paratracheal lymph nodes were demonstrated in almost all of the patients, and a filling defect was observed in three patients, leading to possible metastatic involvement. In seven patients, the right pulmonary hilar lymph nodes were demonstrated, and no node was considered to be metastatic. In three, paraesophageal lymph nodes were preoperatively diagnosed as metastatic. All seven lymph nodes in which metastasis was suspected were confirmed to be metastatic at pathologic examination. The smallest node correctly assessed as metastatic was 6 by 6 millimeters.